Overview

An Open-label, Phase II, Two-stage, Study of Xantrene® (Bisantrene) in combination with Fludarabine and Clofarabine as Salvage Therapy for Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) Lead-in stage: up to 12 (up to 2 cohorts in a 3+3 dose escalation design) Efficacy stage: up to 17 (Simon 2-stage design 9+8)

Study Objectives:

• Confirm safety and tolerability of the combination regimen
• Time to response with combination treatment
• Overall survival

The treatment regimen will comprise daily IV infusion of Fludarabine (Flu), Clofarabine (Clo) and Bisantrene (Xan) administered via central venous line and controlled-rate infusion pump with a 1-hour break between each agent infusion, amounting to a total of 6 hours for each daily FluCloXan treatment in the following sequence:

• First, infusion over 60 minutes of Fludarabine (Flu) at 10 mg/m2
• Followed by infusion of Clofarabine (Clo) at 30 mg/m2 over 60 minutes
• Followed by infusion of Bisantrene (Xan) at 250 mg/m2 over 2 hours. One cycle will comprise daily IV infusion of the combination treatment course for 4 or 5 consecutive days and rest period to between Day 30 and Day 42, based on patient performance and disease status.

Eligibility

Inclusion Criteria:

1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written Informed Consent and privacy language as per national regulations.
2. Age 18 -65 (inclusive) years
3. Diagnosis of AML by World Health Organization (WHO) classification (WHO, 2016) and have received at least one line of therapy prior to enrollment into this study.
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.0
5. Life expectancy ≥ 3 months.
6. Adequate organ function as evidenced by serum total bilirubin ≤ 2.0 mg/dL, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤4 × the upper limit of normal (ULN), serum albumin >2.8 g/dL, serum creatinine ≤2 mg/dL.
7. Cardiac ejection fraction ≥50%, assessed by 2-Dimensional echocardiogram.
8. Pulmonary function ≥50% assessed by diffusing capacity for carbon monoxide (DLCO), and any clinically significant decrease in DLCO must not be caused by infection.
9. Negative for serum markers for HIV, Hepatitis -B, -C, and HTLV-1
10. Clinically significant non-hematologic toxicity after prior chemotherapy has recovered to Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
11. Females must be surgically or biologically sterile or postmenopausal (amenorrhoeic for at least 12 months) or if of childbearing potential, must have a negative urine or serum pregnancy test within 14 days before study entry, and must agree to use an adequate method of contraception, i.e. barrier method, during the study until 30 days after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception, i.e. barrier method, during the study until 30 days after the last treatment.

Exclusion Criteria:

1. Acute promyelocytic leukemia (APML, APL) M3 subtype of AML.
2. Other active malignancy (including other hematologic malignancies) or other malignancy within the last 12 months except non-melanoma skin cancer or cervical intraepithelial neoplasia.
3. Prior or current therapy:
   1. Hydroxyurea or other oral medications to reduce blast count within 72 hours before the first dose of study drug
   2. Treatment with an investigational agent within 14 days before the first dose of study drug, or not recovered from all acute effects of previous investigational therapy
   3. Last treatment was with a drug of long elimination half-life (e.g. enasidenib), as such a wash out period 5x elimination half-life is necessary prior to enrollment
4. For patients who have undergone hematopoietic stem cell transplantation (HSCT),

   procedure-related medications (e.g. immunosuppressive therapy) administered within 2 weeks prior to first dose of study drug.

5. Any medical, psychological, or social condition that may interfere with study participation or compliance or may compromise the patient's safety in the opinion of the investigator.